Neuroserpin gene therapy inhibits retinal ganglion cell apoptosis and promotes functional preservation in glaucoma
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved..
Our research has proven that the inhibitory activity of the serine protease inhibitor neuroserpin (NS) is impaired because of its oxidation deactivation in glaucoma. Using genetic NS knockout (NS-/-) and NS overexpression (NS+/+ Tg) animal models and antibody-based neutralization approaches, we demonstrate that NS loss is detrimental to retinal structure and function. NS ablation was associated with perturbations in autophagy and microglial and synaptic markers, leading to significantly enhanced IBA1, PSD95, beclin-1, and LC3-II/LC3-I ratio and reduced phosphorylated neurofilament heavy chain (pNFH) levels. On the other hand, NS upregulation promoted retinal ganglion cell (RGC) survival in wild-type and NS-/- glaucomatous mice and increased pNFH expression. NS+/+Tg mice demonstrated decreased PSD95, beclin-1, LC3-II/LC3-I ratio, and IBA1 following glaucoma induction, highlighting its protective role. We generated a novel reactive site NS variant (M363R-NS) resistant to oxidative deactivation. Intravitreal administration of M363R-NS was observed to rescue the RGC degenerative phenotype in NS-/- mice. These findings demonstrate that NS dysfunction plays a key role in the glaucoma inner retinal degenerative phenotype and that modulating NS imparts significant protection to the retina. NS upregulation protected RGC function and restored biochemical networks associated with autophagy and microglial and synaptic function in glaucoma.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:31 |
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| Enthalten in: |
Molecular therapy : the journal of the American Society of Gene Therapy - 31(2023), 7 vom: 05. Juli, Seite 2056-2076 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chitranshi, Nitin [VerfasserIn] |
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| Links: |
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| Themen: |
Beclin-1 |
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| Anmerkungen: |
Date Completed 10.07.2023 Date Revised 13.12.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ymthe.2023.03.008 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM354107577 |
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| 245 | 1 | 0 | |a Neuroserpin gene therapy inhibits retinal ganglion cell apoptosis and promotes functional preservation in glaucoma |
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| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Our research has proven that the inhibitory activity of the serine protease inhibitor neuroserpin (NS) is impaired because of its oxidation deactivation in glaucoma. Using genetic NS knockout (NS-/-) and NS overexpression (NS+/+ Tg) animal models and antibody-based neutralization approaches, we demonstrate that NS loss is detrimental to retinal structure and function. NS ablation was associated with perturbations in autophagy and microglial and synaptic markers, leading to significantly enhanced IBA1, PSD95, beclin-1, and LC3-II/LC3-I ratio and reduced phosphorylated neurofilament heavy chain (pNFH) levels. On the other hand, NS upregulation promoted retinal ganglion cell (RGC) survival in wild-type and NS-/- glaucomatous mice and increased pNFH expression. NS+/+Tg mice demonstrated decreased PSD95, beclin-1, LC3-II/LC3-I ratio, and IBA1 following glaucoma induction, highlighting its protective role. We generated a novel reactive site NS variant (M363R-NS) resistant to oxidative deactivation. Intravitreal administration of M363R-NS was observed to rescue the RGC degenerative phenotype in NS-/- mice. These findings demonstrate that NS dysfunction plays a key role in the glaucoma inner retinal degenerative phenotype and that modulating NS imparts significant protection to the retina. NS upregulation protected RGC function and restored biochemical networks associated with autophagy and microglial and synaptic function in glaucoma | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a glaucoma | |
| 650 | 4 | |a neurodegeneration | |
| 650 | 4 | |a neuroserpin | |
| 650 | 4 | |a plasminogen | |
| 650 | 4 | |a retinal ganglion cells | |
| 650 | 4 | |a tissue plasminogen activator | |
| 650 | 7 | |a Beclin-1 |2 NLM | |
| 700 | 1 | |a Rajput, Rashi |e verfasserin |4 aut | |
| 700 | 1 | |a Godinez, Angela |e verfasserin |4 aut | |
| 700 | 1 | |a Pushpitha, Kanishka |e verfasserin |4 aut | |
| 700 | 1 | |a Mirzaei, Mehdi |e verfasserin |4 aut | |
| 700 | 1 | |a Basavarajappa, Devaraj |e verfasserin |4 aut | |
| 700 | 1 | |a Gupta, Veer |e verfasserin |4 aut | |
| 700 | 1 | |a Sharma, Samridhi |e verfasserin |4 aut | |
| 700 | 1 | |a You, Yuyi |e verfasserin |4 aut | |
| 700 | 1 | |a Galliciotti, Giovanna |e verfasserin |4 aut | |
| 700 | 1 | |a Salekdeh, Ghasem H |e verfasserin |4 aut | |
| 700 | 1 | |a Baker, Mark S |e verfasserin |4 aut | |
| 700 | 1 | |a Graham, Stuart L |e verfasserin |4 aut | |
| 700 | 1 | |a Gupta, Vivek K |e verfasserin |4 aut | |
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